2026年9月23日出版的《自然》杂志发表了美国科学家的一项最新研究成果。美国纪念斯隆-凯特琳癌症中心Agnel Sfeir等的最新研究揭示了MMEJ修复TA重复片段的断裂，维持ecDNA和癌症适应度。

染色体外DNA（ecDNA）由兆碱基大小的环状DNA元件组成，常携带癌基因扩增，在许多癌症中驱动侵袭性肿瘤表型、治疗耐药和不良临床结局。尽管ecDNA被认为起源于经典的双链断裂修复，但维持它的通路仍不清楚。在此，研究人员表明，抑制微同源介导的末端连接，而非非同源末端连接或同源重组，可选择性地耗竭ecDNA，诱导ecDNA特异性损伤，并促进其被隔离到微核中，从而损害依赖ecDNA驱动癌基因扩增的癌细胞的适应性。机制上，ecDNA上富含TA的位点是DNA损伤和断裂的热点。DNA转位酶FANCM抑制这些位点处断裂的形成，而逃逸FANCM监视的断裂由ERCC1–ERCC4切割，并被引导进入微同源介导的末端连接进行修复。单细胞全基因组测序显示，在COLO320DM细胞中破坏FANCM或聚合酶θ（Polθ）会导致以缺失和小片段重复为特征的结构不稳定性，其断点富集于富含TA的区域。这种脆弱性在人类肿瘤中得以重现，其中ecDNA重排富集于TA重复序列。总之，研究人员的发现揭示了TA重复序列脆弱性是环状DNA的一种内在弱点，并确定Polθ抑制作为一种有前景的策略，可能使ecDNA不稳定并使ecDNA驱动的肿瘤对治疗干预敏感。

附：英文原文

Title: MMEJ repair of breaks at TA repeats maintains ecDNA and cancer fitness

Author: Billing, David, Selvaraj, Monica, Kelley, Megan E., Matos-Rodrigues, Gabriel, Bailey, Benton, Becker, Finnja, Zhen, Gang, Myers, Matthew A., Brambati, Alessandra, Ezekwenna, Oluchi, Nichols, Ashley, Jiang, Yi-Zhen, Wang, Lucia, Wang, Shih-Chun, Mathieu, Marie-Claude, Pradella, Davide, Poirier, Hugo, Rodriguez-Fos, Elias, Morris, Stephen J., Zimmermann, Michal, Callen, Elsa, Zinda, Michael, Ventura, Andrea, Maciejowski, John, McPherson, Andrew, Shah, Sohrab P., Henssen, Anton George, Nussenzweig, Andr, Sfeir, Agnel

Issue&Volume: 2026-09-23

Abstract: Extrachromosomal DNA (ecDNA) comprises megabase-sized circular DNA elements that frequently carry oncogene amplifications, driving aggressive tumour phenotypes, therapeutic resistance and poor clinical outcomes across many cancers1,2,3,4. Although ecDNA is thought to arise from canonical double-strand break repair, the pathways that maintain it remain unclear. Here we show that inhibition of microhomology-mediated end joining, but not non-homologous end joining or homologous recombination, selectively depletes ecDNA, induces ecDNA-specific damage and promotes its sequestration into micronuclei, compromising the fitness of cancer cells that depend on ecDNA-driven oncogene amplification. Mechanistically, TA-rich loci on ecDNA are hotspots for DNA damage and breakage5,6. The DNA translocase FANCM suppresses break formation at these sites, while breaks that escape FANCM surveillance are cleaved by ERCC1–ERCC4 and channelled into microhomology-mediated end joining for repair. Single-cell whole-genome sequencing shows that disrupting FANCM or polymerase θ (Polθ) in COLO320DM cells causes structural instability characterized by deletions and small duplications, with breakpoints enriched at TA-rich regions. This fragility is recapitulated in human tumours, in which ecDNA rearrangements are enriched at TA repeats. Collectively, our findings reveal TA repeat fragility as an intrinsic vulnerability of circular DNA and identify Polθ inhibition as a promising strategy to potentially destabilize ecDNA and sensitize ecDNA-driven tumours to therapeutic intervention.

DOI: 10.1038/s41586-026-11048-8

Source: https://www.nature.com/articles/s41586-026-11048-8